title: Fragment-to-hit-to-lead discovery of a novel pyridylurea scaffold of ATP competitive dual targeting type II topoisomerase inhibiting antibacterial agents.
abstract: The discovery and optimization of a new class of bacterial topoisomerase (DNA gyrase and topoisomerase IV) inhibitors binding in the ATP domain are described. A fragment molecule, 1-ethyl-3-(2-pyridyl)urea, provided sufficiently potent enzyme inhibition (32 μM) to prompt further analogue work. Acids and acid isosteres were incorporated at the 5-pyridyl position of this fragment, bridging to a key asparagine residue, improving enzyme inhibition, and leading to measurable antibacterial activity. A CF3-thiazole substituent at the 4-pyridyl position improved inhibitory potency due to a favorable lipophilic interaction. Promising antibacterial activity was seen versus the Gram-positive pathogens Staphylococcus aureus and Streptococcus pneumoniae and the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis . Precursor metabolite incorporation and mutant analysis studies support the mode-of-action, blockage of DNA synthesis by dual target topoisomerase inhibition. Compound 35 was efficacious in a mouse S. aureus disease model, where a 4.5-log reduction in colony forming units versus control was demonstrated.
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Basarab
authors.forename: John I
authors.initials: JI
authors.lastname: Manchester
authors.forename: Shanta
authors.initials: S
authors.lastname: Bist
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.forename: Brian
authors.initials: B
authors.lastname: Dangel
authors.forename: Ruth
authors.initials: R
authors.lastname: Illingworth
authors.forename: Brian A
authors.initials: BA
authors.lastname: Sherer
authors.forename: Shubha
authors.initials: S
authors.lastname: Sriram
authors.forename: Maria
authors.initials: M
authors.lastname: Uria-Nickelsen
authors.forename: Ann E
authors.initials: AE
authors.lastname: Eakin
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate; D014508:Urea; D004250:DNA Topoisomerases, Type II